Nerve injuries are a major source of chronic disability. Poor management of nerve injuries is associated with muscle atrophy and can lead to painful neuroma when severed axons are unable to reestablish continuity with the distal nerve. Although nerves have the potential to regenerate after injury, this ability is strictly dependent upon the regenerating nerve fibers (and their axonal sprouts) making appropriate contact with the severed nerve segment (and the Schwann cell basal laminae therein). Regenerating axons that fail to traverse the gap or injury site and enter the basal lamina of the severed distal nerve segment will deteriorate, resulting in neuronal death, muscle atrophy and permanent functional deficit (Fawcett J W et al. [1990] Annu Rev Neurosci 13:43-60).
Briefly, a nerve carries the peripheral processes (or axons) of neurons. The neuronal cell bodies reside in the spinal cord (motor neurons), in ganglia situated along the vertebral column (spinal sensory ganglia) or in ganglia found throughout the organs of the body (autonomic and enteric ganglia). A nerve consists of axons, Schwann cells and extensive connective tissue sheaths (Dagum A B [1998] J Hand Ther 11:111-117). The outer covering, the epineurium, is made of collagenous connective tissue that cushions the fascicles from external pressure and surrounds the perineurium. The perineurium surrounds the individual fascicles and, together with endothelial cells in the endoneurial microvessels, functions as the blood-nerve barrier. The endoneurium lies inside the perineurium and consists of collagenous tissue that surrounds the Schwann cells and axons. A fascicular group consists of two or more fascicles surrounded, respectively, by perineurium and epineurium. The topography of nerves is constant distally, with a group of fascicles being either sensory or motor. The neuron consists of a soma (cell body) and an axon, which can be several feet long.
In nerve injuries where there is axonal disruption, but the continuity of the endoneurial sheath remains intact (e.g., crush injury), axons regenerate within their original basal lamina and complete recovery can be expected. In contrast, axonal regrowth may be severely compromised after nerve transection and surgical repair is highly dependent on the realignment of the nerve elements described above (Dagum A B [1998] J Hand Ther 11:111-117).
Complete regeneration of axons in damaged peripheral nerves is rare. For axon regeneration to occur, regenerative sprouts must enter endoneurial tubes in the distal stump of the nerve (Tona A, Perides G, Rahemtulla F, Dahl D [1993] J Histochem Cytochem 41:593-599; Stoll G, Muller H W (1999) Brain Pathology 9:313-325) where they encounter growth promoting molecules, such as laminin and fibronectin, (Tabb J. S. et al. (1994) J Neurosci 14:763-773; Gorio, A. et al. (1998) Neuroscience 82:1029-1037; Trigg, D. J. et al. (1998) Amer J Otolaryngol 19:29-32; Ferguson, T. A. and D. Muir (2000) Mol Cell Neurosci 16:157-167), as well as molecules that inhibit growth. If the neurons do not make this contact with the distal stump, they will form a neuroma and their growth is disorganized (Sunderland (1978) Fu S Y, Gordon T (1997) Mol Neurobiol 14:67-116.).
Some use of growth factors, to stimulate axon elongation has been used in laboratory animals. The different growth factors act by binding to specific cell surface receptors on neurons, and the different receptors are not found on all neurons in peripheral nerves, only in subsets of them. The major disadvantage of the use of growth factors to promote axon regeneration is this heterogeneity. Not surprisingly, specific growth factors will, at best, promote the outgrowth of axons from only a subset of neurons. The use of nerve growth factor (NGF) in a recent clinical trial illustrates this point. The receptor for NGF, trkA, is found largely on sensory neurons that convey information about painful stimuli. Treatment of patients with diabetic peripheral neuropathy with NGF resulted in a hyperalgesia, an increased sensitivity to painful stimuli, without significant restitution of function of other neuronal types.
Thus, although axons of peripheral nerves can regenerate after being damaged, optimal axonal regeneration in the peripheral nervous system rarely occurs. If endoneurial tubes surrounding individual axons and their ensheathing myelin are damaged beyond repair, there is often little axon regeneration.
At present there are no clinically used therapeutic methods to enhance axon regeneration in peripheral nerves.